Nano-Hybrid Delivery System for Sequential Utilization of Passive and Active Targeting

a delivery system and hybrid technology, applied in the direction of nanocapsules, pharmaceutical delivery mechanisms, capsule delivery, etc., can solve the problems of preventing the clinical translation of polycations in drug delivery

Active Publication Date: 2013-05-16
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]The present invention is a nanohybrid drug delivery composition composed of a multivalent polymeric scaffold with a therapeutic agent and targeting agent attached thereto; and a shell encapsulating the polymeric scaffold. In one embodiment, the shell is a liposome composed of a phospholipid selected from the group of egg phosphatidylcholine, egg phosphatidylethanolamine, soy bean phosphatidylcholine, lecithin, sphingomyelin, synthetic phosphatidylcholine, lyso-phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, and phosphatidylserine, wherein the phospholipid can be modified with a long-circulating agent or cryoprotectant. In another embodiment, the shell is polymeric nanoparticle composed of a polymer selected from the group of poly-(γ-L-glutamylglutamine), poly-(γ-L-aspartylglutamine), poly-L-lactic acid, poly-(lactic acid-co-glycolic acid), polyalkylcyanoacrylate, polyanhydrides, polyhydroxyacids, polypropylfumerate, polyamide, polyacetal, polyether, polyester, poly(orthoester), polycyanoacrylate, [N-(2-hydroxypropyl)methacrylamide] copolymer, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, po

Problems solved by technology

However, toxicity issues related to the strong cationic surface charge have hindered clinical translation of the polycations in drug delivery, largely due to the la

Method used

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  • Nano-Hybrid Delivery System for Sequential Utilization of Passive and Active Targeting
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  • Nano-Hybrid Delivery System for Sequential Utilization of Passive and Active Targeting

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Experimental program
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example 1

Materials and Methods

[0054]Materials.

[0055]Branched PEI (Mn 10,000), PLGA (50:50, Mw 40,000-75,000), poly(vinyl alcohol) (PVA, 87-89% hydrolyzed, Mw 13,000-23,000), rhodamine B isothiocyanate (RITC, mixed isomers), dichloromethane (DCM), pyridine, p-nitrophenyl chloroformate (p-NPC), triethyleamine (TEA), diethyl ether, and cholesterol were all obtained from Sigma-Aldrich (St. Louis, Mo.). Amine-terminated methoxy PEG (mPEG-NH2) (Mw 5,000) was obtained from Nektar (Huntsville, Ala.). 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-mPEG-2000 (DSPE-PEG 2000), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (DOPG) were purchased from Avanti Polar Lipids Inc. (Alabaster, Ala.). All other chemicals used in this study were purchased from Sigma-Aldrich unless specified otherwise.

[0056]Preparation and Characterization of PEI-RITC Conjugates.

[0057]PEI was fluorescently labeled by conjugation with RITC using a similar me...

example 2

Preparation and Characterization of PEI-RITC Conjugates and PEG-PLGA Copolymer

[0082]The UV / Vis measurements revealed the number of RITC molecules attached to a PEI chain. By constructing a calibration curve of UV absorbance of RITC against various concentrations at 555 nm (λmax) the RITC concentration in a solution of the PEI-RITC conjugate was calculated from the absorbance at 555 nm. The molar ratio of PEI and RITC was then calculated by converting the concentration values to number of moles. The results indicated the presence of 6.2 RITC molecules per PEI chain. Particle size and zeta potential of the conjugates were measured to be 11.2 nm and 32.1 mV, respectively (Table 1). In addition, the chemical structure of PEG-PLGA was confirmed by 1H NMR. On the basis of the relative integration values of the characteristic peaks of each polymer, the ratio of the PEG block to the PLGA block was measured to be 1.3:1-2.4:1.

TABLE 1LoadingZeta(μg / mgLoadingParticlePotentialpolymerEfficiencyFo...

example 3

Preparation and Characterization of PEI-RITC-Encapsulated Nanohybrids

[0083]It is highly desirable for a potential tumor-targeted delivery system to possess a size range of less than 200 nm in order to be able to passively accumulate into the tumor tissue. The size of the liposome-based system was controlled by extrusion using a membrane filter with pore size of 100 nm according to a slightly modified method previously described (Ko, et al. (2009) supra). For encapsulation into the polymeric NPs, the double emulsion method was chosen as it enables encapsulation of hydrophilic materials into a variety of polymers or copolymers with a controlled particle size (Perez, et al. (2001) supra; Vauthier & Bouchemal (2009) Pharm. Res. 26:1025-1058). As shown in Table 1, the encapsulation methods employed herein were successful in controlling the size, as particle sizes for all three nanohybrids were in the range of 100-150 nm. Both methods also showed relatively good loading efficiencies (45-9...

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Abstract

The present invention features nanohybrid drug delivery composition which combines both passive and active targeting for the prevention and treatment of disease. The composition is shell-encapsulated multivalent polymeric scaffold with a therapeutic agent and targeting agent attached thereto.

Description

[0001]This application is claims benefit of priority to U.S. Provisional Application Ser. No. 61 / 327,200, filed Apr. 23, 2010, the content of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Multifunctional macromolecules have demonstrated great potential as drug delivery vectors (Nori & Kopecek (2005) Adv. Drug Deliv. Rev. 57:609-636; Patri, et al. (2002) Curr. Opin. Chem. Biol. 6:466-471). In particular, polycationic polymers have been widely explored for many biomedical applications, including gene delivery (Verma & Somia (1997) Nature 389:239-242). One of the most commonly used cationic polymers is polyethylenimine (PEI) that has been primarily used as a nonviral gene delivery vector given its capacity to protect DNA from lysosomal degradation and promote endosomal escape (Boussif, et al. (1995) Proc. Natl. Acad. Sci. USA 92:7297-7301; Gebhart & Kabanov (2001) J. Control. Release 73:401-416; Akinc, et al. (2005) J. Gene Med. 7:657-663; U...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/14
CPCA61K9/1273A61K9/14A61K9/127A61K9/5153A61K9/146
Inventor HONG, SEUNGPYOLIU, YING
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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